Opiate and alpha2-adrenergic receptors have striking similarities pharmacologically, in modulating NE release; biochemically, in occurring together in isolated cells, both receptors being inversely coupled to the same pool of adenylate cyclase in a GTP- and Na ion-dependent manner and showing similar allosteric Na ion and GTP effects in receptor radioligand binding studies; and neuroanatomically, with a very similar regional distribution of sites in the brain. These similarities are of practical importance, since the alpha2-agonist clonidine can attenuate the withdrawal syndrome in opiate-dependent rats and humans. Conversely, patients on alpha2-antihypertensive therapy may experience altered pain threshold and narcotic analgesic efficacy. The object of this proposal is to determine if the opiate and alpha2-receptors are linked in such a way that modulation of one receptor induces a parallel or reciprocal modulation in the other receptor. We have shown that in rat cortex alpha2- and beta-adrenergic receptors are so linked, and show reciprocal modulation after initial beta-receptor activation. Another research goal is to show if the opiate receptor, inversely coupled to adenylate cyclase, is, like the alpha2-receptor, made supersensitive during desensitization of positively coupled beta- and PGE1 receptors. Modulation of opiate and adrenergic receptors will be studied in rat brain slices and homogenates, and NG108-15 cultured cells, after agonist preincubation. Receptor changes will be analyzed by radioligand binding, and also functionally in brain tissue by alpha2- and opiate modification of norepinephrine release. Opiate and dopamine receptor interactions will be similarly examined in rat striatal slices and homogenates.